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Inventors #1
A set of ideas and observations on inventions and discoveries in life sciences.
Immunology
The immune system and everything in it.
An orally available non-nucleotide STING agonist with antitumor activity - https://science.sciencemag.org/content/369/6506/eaba6098 Out of Merck, a group led by George Addona used a phenotypic screen to identify a small molecule, MSA-2, that non-covalently activates STING and is orally available. This is a major breakthrough in the field of innate immunity - the first-generation of STING inhibitors are directly injected into the site of the tumor to avoid degradation. The key insight for why MSA-2 exhibits this property is that it exists in equilibrium between monomers and dimers (this form activates STING) favoring the monomer state, which enables specificity to tumor sites and higher stability.
Cellular backpacks for macrophage immunotherapy - https://advances.sciencemag.org/content/6/18/eaaz6579 - the Mitragotri Lab at Harvard published some really exciting work to develop nanoparticles, which they refer as backpacks, to continuously stimulate (through attachment) macrophages to attack tumors. Macrophages are one of the most flexible immune cell types with regards to involvement in various pathways. Traditional macrophage transfer methods rely on adding free interferon-gamma to bone-marrow derived macrophages to polarize them to the pro-inflammatory M1 state. This backpack concept solves the problem of ensuring macrophages are in the M1 states within the inhibitory TME. This paper along with others shows the power of decoration in the cell therapies:
Evolutionary dynamics of neoantigens in growing tumors - https://www.nature.com/articles/s41588-020-0687-1 - the Graham Lab recently put out some really interesting modeling to predict how neoantigen clonality evolves within a cancer. Neoantigens are cancer-specific peptides that could be useful to target therapies against the cancer. The tricky part is that cancer evolves and figuring out which neoantigen predominates at a given time is very important to know which part of the therapeutic arsenal to use. Building out a stochastic model (validated with cancer RNA-seq data), the paper shows that negative selection within cancers deplete certain neoantigens while still retaining a high tumor mutational burden (TMB). This model is very interesting for all of the immunotherapy combines that are looking for new diagnostic measures to make their medicines more precise and expand indications. TMB might not be a good biomarker to guide immunotherapies:
Biochemistry and structural biology
The granddaddy of them all.
An enumerative algorithm for de novo design of proteins with diverse pocket structures - https://www.pnas.org/content/early/2020/08/20/2005412117 - Benjamin Basanta as the lead author of the paper out of the Baker Lab at the UoW, used de novo design tools and high-throughput screening to design NTF2-superfamily proteins that had to ability to each bind one of 50 ligands chosen. Now who is going to build the cell-free platform to express the millions of de novo designed proteins that are set to transform medicine and the industrial economy.
Neuroscience
Roughly 20 years behind but set up to transform the concept of human.
Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders - https://www.nature.com/articles/s41583-020-0367-2?WT.mc_id=TWT_NatRevNeurosci - this is a really useful review on the usefulness of psychedelics for psychiatric disorders from Frank Vollenweider out of Zurich and Katrin Preller out of Yale. The key drivers for progress in the field over the last few decades has been challenge studies of psychedelics in healthy patients to map out the specific receptors that are engaged. When combined with neuroimaging, the field has gained a good enough understanding of how psychedelics modify the plasticity of the brain. Likely, the next generation of psychiatric medicines will focus and measure brain plasticity. The next steps in the field are to understand the MoAs, replicate the results in larger, randomized trials, and understand the role of psychotherapy in administering these medicines.
Cell biology
Cell structure and function.
Genetically encoded live-cell sensor for tyrosinated microtubules- https://rupress.org/jcb/article/219/10/e201912107/152071/Genetically-encoded-live-cell-sensor-for?searchresult=1 - the Sirajuddin Lab out of InSTEM developed a probe, using a yeast display method, for the terminal tyrosine of alpha-tubulin. Microtubules are very important structures in the cell and dictate movement within the cell. Microtubules have various post-translational modifications (PTM) but this has been a major area of unexplored biology due to the lack of tools. This paper is likely just the beginning in a new sub-field of cell biology focused on tubulin PTMs.
Genetics, genomics, and developmental biology
Heredity and variation.
Phylogenetic structure of the prokaryotic domain: The primary kingdoms - https://www.pnas.org/content/74/11/5088 - onto genetics, a field that was pounded into my head by most of the Harvard MCB faculty. This paper by Carl Woese and George Fox pioneered the use of 16S ribosomal RNA to define the Archaea kingdom of life and forming the basis for our current understanding the origins of life. This is an iconic paper that deserved a Nobel Prize. The old papers are the ones to read more carefully.
How the Microbial World Saved Evolution from the Scylla of Molecular Biology and the Charybdis of the Modern Synthesis - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650883/ - 32 years after the publication of the PNAS paper in 1977, Carl Woese along with Nigel Goldenfeld wrote an incredible review on the Modern Synthesis. I read this paper as a sophomore in college for a microbial sciences class that I originally took to get an easy A. What’s interesting is that In college, the classes that I took as an easy A were the ones I learned the most from. That’s a big reason why I helped get everyone A’s in intro chemistry when I TFed the class as a junior; I wasn’t asked to TF my senior year.
Carl Woese short biography by Norman Pace and Nigel Goldenfeld - https://science.sciencemag.org/content/339/6120/661.summary - after the passing of Carl Woese in 2012, Norman Pace, a pioneer in the biochemistry of RNA, and Nigel Goldenfeld, a leader in astrobiology, wrote a beautiful biography of their colleague.
Daf-2, an Insulin Receptor–Like Gene That Regulates Longevity and Diapause in Caenorhabditis elegans - http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.918.6588&rep=rep1&type=pd - an iconic paper out of the Ruvkun Lab at MGH, one of my scientific mentors. In 1997, the group mapped out the daf-2 gene in C. elegans and mapped out the genetic pathway by which the gene regulates lifespace and the dauer state. Beyond this paper, the Ruvkun Lab’s early focus on dauer worm when very few other groups even were interested, set the Ruvkun Lab up to be the leader in the genetics of longevity and discover microRNAs, which will earn Gary a Nobel Prize. Maybe I’ll start an incubator called DAF-2.
A C. elegans mutant that lives twice as long as wild type - https://pubmed.ncbi.nlm.nih.gov/8247153/ - in 1993, the Tabtlang Lab out of UCSF published the daf-2 mutant with a 2x extended lifespan versus WT.
Construction of a Genetic Linkage Map in Man Using Restriction Fragment Length Polymorphisms - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1686077/pdf/ajhg00189-0020.pdf - this is probably David Botstein’s best paper. In 1980, out of the Ronald Davis Lab at Stanford, Botstein led the research to detect variants in the genome by restriction fragment-length polymorphisms (RFLP). The group used these RFLPs to detect variation in human genomic DNA measured by Southern blots. This was a major breakthrough in the field of genomics, because previous methods relied on enzyme or antigen markers that could not map loci in non-coding regions of the genome. The RFLP method defined the field of genomics and enabled pedigrees and the linkage of genes in disease. Since this paper in 1980, a wide set of diseases have been discovered to have a genetic driver. This paper transformed medicine.